The differentiation of the nervous system depends on a sequence of developmental decisions. These decisions-mediated by cell-cell interactions-include (1) the choice between neural versus non-neural cellular lineages, (2) the subsequent choice among the wide variety of specific neural cell fates, and (3) the choice of appropriate target cells with which to synapse. The long-term goal of this project is to understand the molecular basis of each of these important developmental decisions. In Project A, led by Chris Kintner, we will study the mechanism by which the Notch signaling pathway controls cell fate decisions in the developing vertebrate nervous system. In Project B, led by Martyn Goulding, we will analyze the role that three transcription factors, including Dbx2 and Hfh2, play in determining the identify of the ventral spinal cord interneurons that synapse with motor neurons. In Project C, led by Greg Lemke, we will use loss-of-function and gain-of-function mouse mutants to study the role that receptor protein-tyrosine kinase (PTKs) of the EphA sub-family play in specifying topographically ordered synaptic connections within the developing nervous system. In project D, led by John Thomas, we will study the role of the Derailed receptor PTK in the selection of commissural axon pathways during Drosophila central nervous system (CNS) development. And in Project E, led by Dennis O'Leary, we will study the brainstem and spinal cord of the mammalian CNS. Together, these experiments will provide us with fundamental new insights into the cellular interactions that mediate neural development, and a detailed understanding of their molecular basis.